Pharmaceutical composition containing lipase inhibitor and glucomannan

FIELD: pharmacology, in particular composition and methods for obesity treatment.

SUBSTANCE: claimed composition contains lipase inhibitor, namely orlistat and koniac or glucomannan and pharmaceutically acceptable excipients.

EFFECT: composition preventing gastrointestinal disturbances associated with administration of lipase inhibitor orlistat.

35 cl, 10 ex, 3 dwg

 

The present invention relates to pharmaceutical compositions and methods for the prevention and treatment of obesity. More specifically, the present invention relates to compositions containing a lipase inhibitor, preferably a compound of formula I (orlistat),

and glucomannan, and one or more pharmaceutically acceptable excipients.

Side effects that are sometimes observed in patients undergoing treatment with lipase inhibitors are anal after oil (oily spotting) and fecal incontinence. Oil spotting is the result of physical separation eaten some food fats, but not absorbed from the fecal matter of the colon.

In the US 5447953 it was shown that the absorption of fat may be increased due to a combination of lipase inhibitor with a relatively large amount of water-insoluble coarse fibers. In WO 00/09123 demonstrated that by combining lipase inhibitor, such as orlistat, with small amounts of chitosan, its derivative or salt manifestation anal expiration fat can be significantly reduced.

We discussed various approaches to reduce the expiration of fat. Among the discussed strategies are as follows: 1) the use of surfactants to stabilize Pogranichny the layer of fat/water to prevent coalescence of the fat emulsion in the colon, 2) increase water viscosity in the rectum to reduce both the intensity and frequency of interaction between the droplets and, hence, lowering the possibility of coalescence, 3) physical absorption of fat lipophilic substance or 4) natural increase fecal mass by stimulating bacterial growth in the colon. The latter approach can be implemented either through the use of prebiotic material (e.g., lactobacilli)or through consumption formatiruem fibers acting as a substrate for bacterial growth.

Unexpectedly it was found that koniak, for example, flour Konica, and, especially, glucomannan actively reduce symptoms of gastrointestinal disorders (GI-AE - gastro-intestinal adverse events, gastrointestinal disorders), which are usually observed after application of the lipase inhibitor, as orlistat, or after the use of artificial substitutes for natural fats.

Koniak (Amorphophallus konjac) is a plant from the tubers of which are doing very well known in China and Japan food - flour Konica. This flour, due to the presence in it of glucomannan and water-soluble starches, when interacting with water Sol high viscosity. Glucomannan (formula II) is the main soluble component, it is a polysaccharide consisting of D-glucose and D-mannose. Glucomannan is included as an ingredient in many food products, and finds industrial application in the production of films, liquids for cleaning oils and paints.

M=D-mannose, G=D-glucose

The present invention relates to compositions containing a lipase inhibitor and glucomannan.

In order to avoid misinterpretation of the following definitions in order to illustrate and define the meaning and scope of different concepts used in the description of the present invention.

The term "lipase inhibitor" refers to compounds capable of inhibiting the action of lipase, for example, gastric and pancreatic. Powerful inhibitors of lipases are, for example, orlistat and lipstatin, as described in US 4598089. Lipstatin is a natural product of microbial origin, orlistat is formed by the hydrogenation of lipstatin. Other inhibitors of lipases are a class of compounds commonly known as anglicani. Anglicani are analogues of orlistat (Mutoh etc. in J. Antibiot., 47, 1994,. 1369-1375). The term "lipase inhibitor" also refers to inhibitors of lipases associated with the polymer, such as, for example, described in WO 99/34786 (firm Geltex Pharmaceuticals Inc.). These polymers are characterized by the fact that they are substituted with one group or more than that inhibit lipase. The term "lipase inhibitor" also refers to 2-oxy-4H-3,1-benzoxazin the-4-Onam, described in WO 00/40569 (firm Alizyme Therapeutics Ltd.), for example, 2-decyloxy-6-methyl-4H-3,1-benzoxazin-4-one, 6-methyl-2-tetradecenoic-4H-3,1-benzoxazin-4-one, 2-hexadecenoic-6-methyl-4H-3,1-benzoxazin-4-one and other oxetanone described, for example, in WO 01/32616, WO 01/32669 and WO 01/32670. Most preferably the term "lipase inhibitor" is meant orlistat.

Orlistat is a known compound used for the treatment or prevention of obesity and hyperlipidemia. In the US 4598089, published July 1, 1986, describes a method of obtaining orlistat; US 6004996 describes acceptable pharmaceutical composition. Suitable pharmaceutical compositions are also described, for example, in WO 00/09122 and WO 00/09123. Other ways to get orlistat described in EP-A 185359, EP-A 189577, EP-A 443449 and EP-A 524495.

Preferably orlistat is introduced orally in a dose of from 60 to 720 mg per day in two or three doses. Preferred is the use of a lipase inhibitor in an amount of from 180 to 360 mg, more preferably 360 mg per day, preferably so that this dose was divided and was made the subject of two, particularly three times per day. The subjects are mostly obese people or people with excess weight, such as those with a body mass index is 25 or more. Generally preferred is the use of a lipase inhibitor in connection with the consumption of fatty foods and on-time PR is about should be within one to two hours relative to the time of food consumption.

Orlistat may be people in conventional oral compositions, such as tablets, coated tablets, hard and soft gelatine capsules, emulsions or suspensions. Examples of media that can be used for tablets, coated tablets, dragées and hard gelatin capsules are lactose, other sugars and sugar alcohols such as sorbitol, mannitol, maltodextrin or other fillers; surfactants such as sodium lauryl sulfate, Brij 96 or Tween 80; leavening agents such as sodium salt starch glycolate, corn starch or derivatives thereof; such polymers, as povidone and crosspovidone; talc; stearic acid or its salts, etc. are Acceptable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like, moreover, the pharmaceutical preparations can contain preserving agents, solvents, stabilizing agents, moisturizers, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, coating agents and antioxidants. They can also contain other therapeutically valuable compounds. The compositions can be traditionally presented in the form of a single dose and can be prepared by any method known in pharmacology. Preferably the orlistat is used in the compositions, shown in the examples of the present invention and in US 6004996.

The term "flour Konica" refers hydrocolloid polysaccharide obtained from the tubers of Amorphophallus konjac. Long tubers of this plant found in Asia and specially cultivated in Japan. Flour Konica is a high molecular weight nonionic glucomannan, which mainly consists of molecules of mannose and glucose in a molar ratio of 1.6:1.0 in. It is often weakly branched polysaccharide, coupled beta 1-4 bonds, molecular weight ranging from 200,000 to up to 2,000,000 daltons. Acetyl groups along the chain of glucomannan provide its solubility, they occur at an average frequency one group 9-19 sugar monomers. Refined flour Konica soluble in cold water to form a viscous solution with a pH of from 4.0 to 7.0. The introduction of alkaline solution leads to the formation of heat-resistant gel that is resistant to melting, even in conditions of prolonged heating. The process of cleaning the flour Konica is conducted on large-scale extraction plants. Tubers Konica first crushed and then the obtained particles glucomannan grind in order to dislodge and remove harmful materials, coupled with them. As a result of this get refined flour Konica high purity, which improves the solubility, stability and overall functional is ity of the product. Particles of treated flour Konica white, without taste and smell.

Flour Konica and glucomannan (products PROPOL®and RHEOLEX®) are commercially available (firm Kyoei Konnyaku, Inc., Behr, Wunderlich & Co., Provisco, FMC Biopolymers, Naturland, SiberHegner and Co. Ltd). Preparation and use are described, for example, in US 3767424, US 3973007, US 4588589, US 5486364, US 5486364, US 5733593, US 5536521, US 6126906 etc.

Used in the present invention the term "pharmaceutically acceptable" refers to compounds that are acceptable from the point of view of their toxicity.

More specifically the present invention relates to a pharmaceutical composition comprising a lipase inhibitor and glucomannan. Optimally, this composition may contain one or more pharmaceutically acceptable excipients. Glucomannan can be used in the form of Konica. Preferably koniak contains not less than 80% of glucomannan, more preferably at least 90% of glucomannan. Glucomannan from kanyaka can be used in the form of powder Konica, for example, flour Konica. A preferred lipase inhibitor is orlistat.

Pharmaceutical compositions containing the compound is a lipase inhibitor and glucomannan are important embodiments of the present invention. Such pharmaceutical compositions contain a pharmaceutically effective amount of each of the compounds. Each dose unit mo is no contain daily doses of both compounds or a part of their daily doses, for example, the third. In addition, each unit dose may contain a dose of one of the compounds and of the doses of other compounds. In this case, the patient should daily take one of the combined dose units and one or more units containing only other component.

In a preferred embodiment of the present invention the composition comprises a) from 0.1 to 20 wt.% the lipase inhibitor, b) from 10 to 75 wt.% Konica and C) from 0.1 to 90 wt.% one or more pharmaceutically acceptable excipients. More preferably the composition may contain from 0.1 to 10 wt.% the lipase inhibitor, b) from 20 to 75 wt.% glucomannan and C) from 0.1 to 90 wt.% one or more pharmaceutically acceptable excipients. Preferably the amount of one or more of pharmaceutically acceptable excipients is from 5 to 50%, more preferably from 5 to 20%. More specifically, the composition may contain (a) from about 5 to 1000 mg of a lipase inhibitor, such as orlistat, about 10 to 500 mg of a lipase inhibitor, preferably from about 20 to 100 mg of a lipase inhibitor, for example from about 10 to 360 mg of orlistat, more preferably from about 30 to 120 mg of orlistat, more preferably from about 40 to 80 mg of orlistat and b) from about 0.5 to 10 g glucomannan, preferably from about 0.5 to 8 g glucomannan, more preferably PR is approximately from 0.5 to 6 g glucomannan.

Pharmaceutically acceptable excipients may be selected from the group consisting of fillers, surfactants, disintegrating agents, binders, lubricants, enhancers speed removing, sweeteners, colorants, for example, the composition can include (a) about 5 to 1000 mg of a lipase inhibitor; b) from about 0.5 to 10 g glucomannan; and optionally pharmaceutically acceptable excipients selected from the group and representing from about 0.1 to 10 g of fillers, from about 0.05 to 5.0 g of surfactants, from about 0.05 to 2.0 g of baking powder, from about 0.02 to 5.0 g of the binder, from about 0.001 to 1.0 g of lubricants, from about 0.1 to 5.0 g of amps speed removing, from about 0.01 to 4.0 g of sweetener and from about 0.001 to 0.5 g dye.

Pharmaceutically acceptable excipients may be selected from the group consisting of fillers, such as sugars and/or sugar alcohols, such as lactose, sorbitol, mannitol, maltodextrin, and others; surfactants such as sodium lauryl sulfate, TPGS, Brij 96 or Tween 80; disintegrating agents, for example sodium salt starch glycolate, corn starch or derivatives thereof; binders such as povidone, crosspovidone, polyvinyl alcohol, hypromellose; lubricants, for example terenowy acid or its salts; amplifiers removing, for example silicon dioxide; sweeteners, such as aspartame; and/or dyes, for example β-carotene.

In the preferred embodiment of the present invention the composition comprises a) from about 0.1 to 20% (wt./mass.) the lipase inhibitor; b) from 10 to about 75% (wt./mass.) glucomannan; optionally selected from the group of pharmaceutically acceptable excipients: from about 0.1 to 20% (wt./mass.) fillers, from about 0.1 to 10% (wt./mass.) baking powder, from about 0.1 to 10% (wt./mass.) bonding agents, from about 0.1 to 10% (wt./mass.) lubricants, from about 0.1 to 10% (wt./mass.) accelerators removing, from about 0.1 to 10% (wt./mass.) sweetener and from about 0.1 to 5% (wt./mass.) the dyes.

In more detail the composition may contain (a) from about 5 to 1000 mg of a lipase inhibitor, such as orlistat, in quantity, for example, about 10 to 500 mg of a lipase inhibitor, preferably from about 20 to 100 mg of a lipase inhibitor, for example, about 10 to 360 mg of orlistat, more preferably from about 30 to 120 mg of orlistat, more preferably from about 40 to 80 mg of orlistat and b) from about 0.5 to 10 g glucomannan, preferably from about 0.5 to 8 g glucomannan, and more preferably from about 0.5 to 6 g glucomannan.

Dose forms for oral administration are PR is doctitle compositions for use according to the present invention and the known pharmaceutical forms for such application, for example, tablets, capsules, discs, sachets, granules, syrups and aqueous or oil suspensions. Pharmaceutically acceptable excipients (solvents and carriers), known in the pharmaceutical industry. Tablets can be obtained from a mixture of active ingredients with extenders, for example with calcium phosphate; disintegrating agents such as corn starch, and lubricating agents such as magnesium stearate; binders, such as microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the art, for tableting the mixture by known methods. Similarly, for example, known methods can be made hard or soft gelatin capsules, containing the active compound with or without the addition of excipients. The contents of the capsules can be by known methods designed to obtain a prolonged release of the active compounds. For example, useful in each tablet and capsule can contain a number of lipase inhibitor and glucomannan, as described above.

Other dose forms for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium form carboxymetilcellulose is, and oily suspensions containing the active compound in suitable for this purpose vegetable oil, such as peanut, olive or myritol 318. Active compounds may contain granules that contain or do not contain additional excipients. Granules can be directly proglatavetsa patient or previously they can be made in a suitable liquid carrier (e.g. water). Granules can contain leavening agents, for example, a couple of compounds, an acid and a carbonate or bicarbonate, to obtain a fizzy drink and easier dispersion in a liquid medium.

In the compositions of the present invention the active compounds can, optionally, be associated with other acceptable pharmacologically active ingredients. In addition to the compounds of the present invention can be applied vitamins.

Both compounds, a lipase inhibitor and glucomannan can be applied simultaneously, separately or sequentially (e.g., orlistat, as shown above, and glucomannan in the evening). Preferably the compound or composition, take with food or within 1 or 2 hours before or after a meal. The doctor decides on the number of glucomannan, which should take the patient, taking into account a number of factors, including the patient's age, weight status and history.

the present invention also relates to compositions, as described above, used for the treatment and prevention of obesity, and to a method for preparing compositions as described above, which consists in mixing lipase inhibitor with glucomannan and optionally one or more pharmaceutically acceptable excipients.

The present invention also relates to a kit for the treatment of obesity, which includes a first component, a lipase inhibitor and b) the second ingredient is glucomannan, as described above, for example, a total dose form for oral administration, preferably contain from 1 to 100 dose units orlistat and b) from 1 to 100 dose units glucomannan.

Another embodiment of the present invention is a kit for the treatment of obesity, which includes a first component, a lipase inhibitor and b) the second ingredient is glucomannan in a single oral dose forms.

The present invention also relates to the use of a composition as described above, upon receipt of medicinal products intended for the treatment and prevention of obesity and for the application of the lipase inhibitor, upon receipt of a medicinal product for the treatment and prevention of obesity in patients who are also taking glucomannan. The use of glucomannan and lipase inhibitor refers to the simultaneous, separate or sequential use for the treatment and prevention of obesity. Further, the present invention relates to a method of treatment of obesity in people in need of such treatment, which consists in applying a therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of glucomannan, as described above. The method relates to the simultaneous, separate or sequential use of these compounds. Another embodiment of the present invention is a lipase inhibitor and glucomannan or koniak, as described above, as a combined preparation for simultaneous, separate or sequential use for the treatment and prevention of obesity. The present invention also relates to the use of glucomannan or Konica, as described above, to obtain drugs that are useful for the treatment and prevention of gastrointestinal side effects selected from the group comprising oily spotting, fatty/oily stools, frequent urge for defecation, increased defecation and incontinence, as well as to a method of treatment or prevention of gastrointestinal side effects selected from the group comprising oily spotting, fatty/oily stools, frequent urge for defecation, increased defecation and involuntary stool, designed for people who need in such treatment, and seeks to apply terap whitesky effective amount of Konica or glucomannan, as specified above. Also the present invention relates to a lipase inhibitor and glucomannan or kayaku, as indicated above, for simultaneous, separate or sequential use for the treatment and prevention of obesity.

The invention will be understood better if we consider the reference to the following examples which illustrate, but not limit, described by the present invention.

DRAWINGS

Figure 1 shows the tested emulsion Konica after centrifugation at 3100 g for t=1 min (a) and t=300 min (b), respectively. After centrifugation for t=300 min weak stabilization was observed only in emulsions containing koniak in concentrations exceeding 1,5% (wt./mass.).

Figure 2 shows the tested emulsion Konica after centrifugation at 3100 g for t=1 min (a) and t=300 min (b), respectively. The emulsions contain a 1.0% (wt./mass.) Konica and have different pH values. After centrifugation for t=300 min small stabilization was observed in the emulsions with pH 6 and 7, respectively. In all other emulsions were observed coalescence.

Figure 3 shows the effect of different types of glucomannan, expressed in percentage of the control, reduction of free oil (presents averages ±SE*).

* the standard deviation of estimates

EXAMPLES

NOTE THE R 1: in vitro studies

Unexpectedly, it was found that glucomannan minimizes gastrointestinal side effects (GI-AE), usually observed after application of the lipase inhibitor, as orlistat.

The interaction of kanyaka (source glucomannan) with butter and water was investigated using absorption test. Samples of the compounds are brought into contact with either soybean oil or artificial intestinal fluid (simulated intestinal fluid - SIF - phosphate buffer without Pancreatin), and incubated 24 hours at 37°C. the Remaining liquid was separated from the solid material by centrifugation (3×5 min at 3100 g). In SIF observed a significant swelling of the polymer in soy oil swelling was not. The absorptive capacity of Konica in SIF and soybean oil was determined as 4.8 and 0.5 g/g, respectively. Koniak has low lipophilicity, because it binds to a small amount of oil.

The ability of the emulsions stabilized with konakom to coalescence was investigated using the centrifugation method. Using this method, carried out in vitro, we examined the stability of the emulsion, depending on concentration and pH. The results of the stability studies are shown in tables 1 and 2. When the concentration of Konica less than 0.5% (wt./mass.) emulsions were highly unstable, which was reflected in the rapid separation of oil/water (PL. 1)if you Didn concentration kanyaka of 1.0% (wt./mass.) emulsions remain quite unstable and after a 10 min centrifugation clearly divided into phases. Only emulsion containing more than 1.0% (wt./mass.) Konica, after centrifugation, lasting up to t=300 min, showed average stability, but the emulsion was partially disrupted (Figure 1).

Table 1
The experimental stability of emulsions with konakom depending on the concentration (C) and centrifugation time (t)
Concentration (%, mass./mass.)The stability of emulsions with konakom (t/min)
1104070100130160220300
0,01n*nnnnnnnn
0,1nnnnnnnnn
0,5nnnnnnnnn
1,0nnnnn nn
1.5in

Concentration (%, mass./mass.)The stability of emulsions with konakom (t/min)
1104070100130160220300
2,0in

*n=low stability: oil and water form two clearly separated phases; C=average stability: emulsion partially broken; in=high stability: no signs of coalescence, optically opaque stable emulsion.

Figure 1 shows the status of the experimental emulsions Konica after centrifugation at 3100 g for 1 min (a) and 300 min (b), respectively. After centrifugation for 300 min only in emulsions containing koniak at concentrations above 1.5% (wt./mass.), observed mild stability.

In order to investigate the stability of the emulsion at different pH values was studied EMU is see with a constant concentration of kanyaka (C=1,0%, mass./mass.) at different pH values from 4 to 9 (table. 2). When both extreme pH values (4 and 9) observed a very weak emulsification experimental emulsions, which was reflected in the instantaneous appearance of the oil phase. At pH=8 and centrifugation time is not more than 30 min was also observed in complete destruction of the emulsion, the emulsion at pH=5 was a little more stable. In this experiment, coalescence occurred when the duration of centrifugation over 60 minutes From the point of view of stability of the emulsion is optimal pH from slightly acidic to neutral (pH 6-7).

Table 2

The experimental stability of emulsions with konakom depending on the pH and duration of centrifugation (t)
pHThe stability of emulsions with konakom (t/min)
13060120300
4n*nnnn
5nn
6
7
8nnnn
9nnnnn

*n=low stability: oil and water form two clearly separated phases; C=average stability: emulsion partially broken; in=high stability: no signs of coalescence, optically opaque stable emulsion.

Figure 2 shows the status of the emulsions with konakom after centrifugation at 3100 g for 1 min (a) and 300 min (b), respectively. The emulsion contained a 1.0% (wt./mass.) Konica at different pH values. After centrifugation at t=300 min weak stability of the emulsions was observed at pH 6 and 7, respectively. In the rest of the emulsions was observed intense coalescence.

To prepare solutions of concentrations Konica 0,01%, 0,1%, 0,5%, 1,0%, 1,5% and 2.0% (wt./mass.) in artificial intestinal fluid (SIF) without Pancreatin according to the method described in USP XXII, s (pH=7.5, the buffer on the basis of one-deputizing potassium phosphate). To 18 g of this solution was added 2 g of soybean oil (catalogue company FLUKA, 85471) and eventually received content of the soybean oil to the water phase, equal to 10% (wt./mass.). Soybean oil was not purified. Then prepared em is lsii, using the apparatus for microgametogenesis (28000 rpm) (E), the time of homogenization was 1 min. it Should be noted that a mixture of soybean oil and water were prepared without the addition of surfactants. Colouring emulsion dye Nile red and the subsequent analysis using an optical microscope revealed that the emulsions were of type oil-type. Immediately after preparation of the emulsions were measured using a device Galai CIS-1, the average droplet size; they were generally 20-30 microns. Glass capillaries with a height of 95 mm and a diameter of 1.7 mm (thickness 0.8 mm) with a syringe filled with the prepared slurry to a height of 6.5 cm and centrifuged at maximum speed 5000 rpm, Eppendorf centrifuge 5403, rotor No. A-44), which corresponded to the centrifugal force 3100 g (with respect to the bottom of the glass capillary). In order to fix the process of breaking emulsions, centrifugation was interrupted at regular intervals (t=1, 10, 40, 70, 100, 130, 160, 220, 300 min) and the capillary was placed on the optical scanner, acting on the transmission type (the instrument Bio-Rad GS-700 Imaging Densitometer).

The distance between the capillary was maintained constant using makeshift tripod. All measurements were carried out at room temperature.

EXAMPLE 2: 1 in vivo

To identify compounds that could the t in the treatment orlistat reduce side effects, associated with oil, was developed a model of acute experiments on people.

Healthy volunteers received for 3 consecutive meals only orlistat or orlistat, in combination with the test compound (test three meals). Modified compositions of orlistat used in the test, three meals, caused the removal of 70-80% fat. Volunteers were given a questionnaire to record side effects. The most serious side effect associated with oil was the oil spotting (uncontrolled oil separation). This side effect is difficult to quantify in acute experiments, however, some volunteers were observed spontaneous separation of the fat from feces. This fat is called free oil (mainly containing triglycerides), was isolated and weighed.

The amount of free oil was used as a surrogate marker for oily spotting, because it was considered that it is necessary for the emergence of oil spotting.

To examine the modifying effect of various compounds in relation to the disturbances of the gastrointestinal tract was conducted two clinical studies. It turned out that the volunteers have different individual sensitivity to side effects caused by orlistat and prowl is available in the gastrointestinal tract. For this reason, each volunteer was its own control (using only one orlistat). Volunteers showed weak sensitivity to side effects caused by orlistat, was not taken into account. For volunteer connection was estimated as the current is positive when the amount of free oil was reduced by at least 50% compared with the control group (receiving only one orlistat).

Glucomannan tested in the form of powder Konica. Powder Konica obtained from the roots of the tree ((Amorphophallus konjac), which is the natural source of glucomannan. This compound was tested in a model of acute side effects in the dose of 4 g/meal. Among the five studied volunteers from four to 50% decreased the amount of free oil in comparison with experiments, which did not use glucomannan (see tab. 3). The volunteers who took glucomannan/orlistat was not observed decrease the excretion of fat (compared with volunteers who took only one orlistat, data not shown), which confirms the lack of correlation of glucomannan with orlistat. Reports of significant side effects associated with taking glucomannan, was not.

Table 3
The results of studying the influence is of Onaka (glucomannan)
Glucomannan (koniak, 4 g/meal)The formation of free oil (g/week)
OrlistatOrlistat + koniak
Study 1118
90
3916
Study 2178
406
Positive results / total (50%<control)4/5

EXAMPLE 3: II in vivo

The results of experiments in vitro were further supported by studies performed in vivo in mice as a model object. This experiment was based on the observation lies in the fact that when the content of the mice on the rich fat diet with the introduction of orlistat or other lipase inhibitor, during grooming animals distribute eye-catching free oil on the fur. Researched several types and compositions of glucomannan to test their ability to reduce or eliminate the release of free oil. The results are presented in figure 3.

EXAMPLE 4: pharmaceutical compositions of orlistat

A)

Ingr dirty Number

(mg/capsule)
Orlistat120,00
Microcrystalline cellulose (AVICEL PH-101)93,60
Sodium salt of starch glycolate PRIMOJEL)7,20
Sodium lauryl sulfate7,20

IngredientsQuantity (mg/capsule)
Polyvinylpyrrolidone (Povidone K-30)12,00
Talc0,24
Only240,24 mg

Method.

1. Mix in a suitable mixer orlistat, microcrystalline cellulose and sodium salt starch glycolate.

2. Be pelletized with a solution of polyvinylpyrrolidone and sodium lauryl in purified water.

3. Skip the granulate through the extruder and then the resulting extrudate to pass through a molder to produce spherical pellets.

4. Dry the pellets at a temperature of 30°C.

5. Add talc and mix.

6. Be placed in hard gelatin capsules.

B)

IngredientsQuantity (mg/capsule
Orlistat60
Microcrystalline cellulose46,8
Sodium salt of starch glycolate3,6
Sodium lauryl sulfate3,6
Polyvinylpyrrolidone6,0
Talc0,12
Only120,12 mg

Method.

1. Mix in a suitable mixer orlistat, microcrystalline cellulose and sodium salt starch glycolate.

2. Be pelletized with a solution of polyvinylpyrrolidone and sodium lauryl in purified water.

3. Skip the granulate through the extruder and then the resulting extrudate to pass through a molder to produce spherical pellets.

4. Dry the pellets at a temperature of 30°C.

5. Add talc and mix.

6. Be placed in hard gelatin capsules.

In)

IngredientsQuantity (mg/capsule)
Orlistat60120
Lactose4080
Microcrystalline cellulose60120
Sodium lauryl sulfatethe 5.711,4
Sodium salt of starch glycolate2040
Polyvinylpyrrolidone 1020
Talc0,20,4
Only195,9 mg391,8 mg

Method.

1. Mix in a suitable mixer orlistat, lactose, microcrystalline cellulose and sodium salt starch glycolate.

2. Be pelletized with a solution of polyvinylpyrrolidone and sodium lauryl in purified water.

3. Skip the granulate through the extruder and then the resulting extrudate to pass through a molder to produce spherical pellets.

4. Dry the pellets at a temperature of 30°C.

5. Add talc and mix.

6. Be placed in hard gelatin capsules.

EXAMPLE 5: pharmaceutical compositions of glucomannan

Composition:

IngredientsQuantity (g/chewable pill)
Glucomannan1,5
Sorbitol1,1
Anhydrous lactose0,376
Talc0,16
The sodium fumarate0,064
Only3,2

Method.

1. Mix in a suitable mixer glucomannan, sorbitol and lactose.

2. Skip the resulting powder through a sieve.

3. Add talc, saariluoma is tons of sodium and mix.

4. Immediately extruding the powder mixture in chewable tablets.

EXAMPLE 6: pharmaceutical compositions of glucomannan

Composition:

IngredientsQuantity (g/sachet)

Glucomannan4
Aspartame0,5
Beta carotene0,001
Only4,501

Method.

1. Suitable mixer to fill the glucomannan.

2. Be pelletized with a solution/colloidal suspension of aspartame and beta-carotene in purified water.

3. Dry the granules at a temperature of 60°C.

4. Skip the granules through a sieve.

5. Place into the sachet.

EXAMPLE 7: a pharmaceutical composition glucomannan

Composition:

IngredientsQuantity (g/chewable pill)
Glucomannan0,5
Lactose0,5
Microcrystalline cellulose1,31
Sodium lauryl sulfate0,09
Sodium salt of starch glycolate0,3
Polyvinylpyrrolidone0,15
Talc0,15
Only3,0

Method.

1. Mix in a suitable mixer glucomannan, lactose, microcrystalline cellulose and sodium salt starch glycolate.

2. In purified water to dissolve sodium lauryl sulfate, and polyvinylpyrrolidone.

3. Be pelletized with the obtained solution.

4. Skip the granulate through the extruder and then the resulting extrudate to pass through a molder to obtain rounded pellets.

5. Dry the pellets at 65°C.

6. Add talc and mix.

7. To compress the pellets in chewable tablets.

EXAMPLE 8: pharmaceutical compositions of orlistat/glucomannan

Composition:

IngredientsQuantity (g/chewable pill)
Orlistat0,06
Glucomannan0,75
Lactose0,5
Microcrystalline cellulose1,31
Sodium lauryl sulfate0,09
Sodium salt of starch glycolate0,3
Polyvinylpyrrolidone0,15
Talc0,15
Only3,31

Method.

1. Amuse is in a suitable mixer orlistat, glucomannan, lactose, microcrystalline cellulose and sodium salt starch glycolate.

2. In purified water to dissolve sodium lauryl sulfate, and polyvinylpyrrolidone.

3. Be pelletized with the obtained solution.

4. Skip the granulate through the extruder and then the resulting extrudate to pass through a molder to obtain rounded pellets.

5. Dry the pellets at a temperature not exceeding 35°C.

6. Add talc and mix.

7. To compress the pellets in chewable tablets.

EXAMPLE 9: the pharmaceutical compositions of orlistat/glucomannan

Composition:

IngredientsQuantity (g/sachet)
Orlistat0,12
Glucomannan4
Sucrose2,8
Beta carotene0,001
Silicon dioxide0,5
Only7,421

Method.

1. Mix in a suitable mixer orlistat, glucomannan and sucrose.

2. Mix a few tricks with a mixture of beta carotene and silicon dioxide.

3. Place into the sachet.

EXAMPLE 10: pharmaceutical compositions of orlistat/glucomannan

Composition:

Ingredients Quantity (g/chewable pill)
Orlistat0,12
Glucomannan2,0
Sodium salt of starch glycolate0,1
Microcrystalline cellulose0,2
Sodium lauryl sulfate0,03
Crosspovidone0,1
Aspartame0,15
Talc0,15
Magnesium stearate0,03
Only2,85

Method.

1. Mix in a suitable mixer orlistat, glucomannan, microcrystalline cellulose, sodium salt of starch glycolate and crosspovidone.

2. Be pelletized with a solution/colloidal suspension lauryl sodium and aspartame in purified water.

3. Skip the granules through a sieve.

4. Dry the granules at 30°C.

5. Skip the dried granules through a sieve.

6. Mixed with talc and magnesium stearate.

7. Be compressed into chewable tablets.

1. Pharmaceutical composition for the treatment and prevention of obesity, comprising a lipase inhibitor such as orlistat and glucomannan or koniak.

2. The composition according to claim 1, additionally comprising one or more pharmaceutically acceptable excipients.

3. Pharma is eticeskaja composition according to claim 1, including koniak.

4. The pharmaceutical composition according to claim 3, in which koniak contains not less than 80% of glucomannan.

5. The pharmaceutical composition according to claim 4, in which koniak contains not less than 90% of glucomannan.

6. The pharmaceutical composition according to claim 5, in which koniak or glucomannan presents the flour Konica.

7. The composition according to claim 1, in which the inhibitor of lipid is orlistat.

8. The composition according to claim 1, in which the composition includes

a) from 0.1 to 20 wt.% the lipase inhibitor,

b) from 10 to 75 wt.% Konica and

C) from 0.1 to 90 wt.% one or more pharmaceutically acceptable excipients.

9. The composition according to claim 8, including

a) from 0.1 to 10 wt.% the lipase inhibitor,

b) from 20 to 75 wt.% glucomannan and

C) from 0.1 to 90 wt.% one or more pharmaceutically acceptable excipients.

10. The composition according to claim 1, including

a) from about 5 to about 1000 mg of a lipase inhibitor, and

b) from 0.5 to about 10 g glucomannan.

11. The composition of claim 10 comprising from about 0.5 to 8 g glucomannan.

12. The composition according to claim 11, comprising from about 0.5 to 6 g glucomannan.

13. The composition according to claim 1, in which the pharmaceutically acceptable excipient selected from the group consisting of fillers, surfactants, leavening agents, bonding agents, lubricating substances which, accelerators removing, sweeteners and dyes.

14. The composition according to claim 2, including

a) from about 5 to about 1000 mg of a lipase inhibitor,

b) from about 0.5 to about 10 g glucomannan and optional pharmaceutically acceptable excipients selected from the group of: from about 0.1 to about 10 g of fillers, from about 0.05 to about 5.0 g of surfactants, from about 0.05 to about 2.0 g of baking powder, from about 0.02 to about 5.0 g connecting substances, from about 0.001 to about 1.0 g of lubricants, from about 0.1 to about 5.0 g accelerators removing, from about 0.01 to about 4.0 g of sweetener and from about 0.001 to about 0.5 g dye.

15. The composition according to claim 2, including

a) from about 0.1 to about 20 wt.% the lipase inhibitor,

b) from 10 to about 75 wt.% glucomannan and optionally selected from the group of pharmaceutically acceptable excipients: from about 0.1 to about 20 wt.% fillers, from about 0.1 to about 10 wt.% surface-active agents, from about 0.1 to about 10 wt.% baking powder, from about 0.1 to about 10 wt.% bonding agents, from about 0.1 to about 10 wt.% lubricants, from about 0.1 to about 10 wt.% accelerators removing, from about 0.1 to about 10 wt.% sweetener and from about 0.1 to PR is about 5 wt.% the dyes.

16. The composition according to 14 or 15, in which the lipase inhibitor is orlistat.

17. The composition according to claim 1, comprising about 10 to 500 mg of a lipase inhibitor.

18. The composition according to claim 1, comprising from about 20 to 100 mg of lipase inhibitor.

19. The composition according to claim 1, comprising from about 10 to 360 mg of orlistat.

20. The composition according to claim 1, comprising from about 30 to 120 mg of orlistat.

21. The composition according to claim 1, comprising from about 40 to 80 mg of orlistat.

22. The composition according to claim 1, comprising from about 0.5 to 8 g glucomannan.

23. The composition according to claim 1, comprising from about 0.5 to 6 g glucomannan.

24. The composition according to claim 1 for use in the treatment and prevention of obesity.

25. A method of obtaining a composition according to any one of claims 1 to 23, which consists in mixing inhibitor of lipase with glucomannan and optionally one or more pharmaceutically acceptable excipients.

26. Set for the treatment of obesity, which contains a first component, a lipase inhibitor and (b) the second component, glucomannan, in the form of individual doses for oral administration.

27. The use of a composition according to any one of claims 1 to 24 to obtain drugs used for the treatment and prevention of obesity.

28. The use of a lipase inhibitor, as described in any one of claims 1 to 23, to obtain medicines used for the treatment and prevention of obesity patients is now, who also get glucomannan as described in any one of claims 1 to 27.

29. Use p for simultaneous, separate or sequential use for the treatment or prevention of obesity.

30. A method of treating obesity in humans in need of such treatment, which consists in applying a therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of glucomannan as described in any one of claims 1 to 23.

31. The method according to item 30 for simultaneous, separate or sequential use.

32. A lipase inhibitor and glucomannan or koniak as specified in claims 1 to 23, for simultaneous, separate or sequential use for the treatment and prevention of obesity.

33. A lipase inhibitor and glucomannan or koniak as specified in claims 1 to 23, as a combined preparation for simultaneous, separate or sequential use for the treatment and prevention of obesity.

34. The use of glucomannan or Konica as specified in claims 1 to 23 for the preparation of drugs suitable for the treatment and prevention of gastrointestinal side effects selected from the group including oily spotting, fatty/oily stools, frequent urge for defecation, increased defecation and incontinence.

35. Method for the treatment or prevention of gastrointestinal side E. the effects selected from the group including oily spotting, fatty/oily stools, frequent urge for defecation, increased defecation and incontinence, among people in need of such treatment, which consists in assigning the patient a therapeutically effective amount of Konica or glucomannan as described in any one of claims 1 to 23.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinazoline of the general formula (I): , wherein R1 represents -O-R4 or -N(R5)(R6); R2 represents alkyl; R3 represents hydrogen atom; R4 represents hydrogen atom, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, pyridinylalkyl substituted with cyano-group or halogen atom, cycloalkylalkyl; R5 and R6 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, arylcarbonyl, alkoxyalkyl, hydroxyalkyl, pyridinyl, furanylcarbonyl, or R5 and R6 in common with nitrogen atom (N) to which they are added form a 5-10-membered heterocyclic ring that comprises optionally the second heteroatom chosen from nitrogen or oxygen atoms and wherein heterocyclic ring is substituted optionally with one or some substitutes chosen independently from alkyl or alkoxy-group; A represents 5-7-membered heterocyclic ring comprising nitrogen atom added to quinazoline ring, and optionally the second heteroatom that is chosen from oxygen, sulfur or nitrogen atoms and wherein ring A is substituted optionally with one or some substitutes chosen independently from alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, and their pharmaceutically acceptable salts and esters. Also, invention relates to a method for synthesis of compounds of the formula (I) and to pharmaceutical composition possessing antagonistic activity with respect to neuropeptide Y. Invention provides synthesis of novel biologically active compounds and pharmaceutical compositions based on thereof possessing antagonistic activity with respect to neuropeptide Y.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 34 ex

FIELD: medicine, in particular, obesity treatment methods.

SUBSTANCE: method involves using food additive such as silica gel which is added in an amount of 100-1,000 g per day before/after or instead of each taking of food, with course time making from 2 weeks to 96 weeks.

EFFECT: increased efficiency in gradual loosing of weight, elimination of sensation of hunger, clearing of organism from residue and toxins, simplified application of method and reduced expenses for treatment procedures.

3 ex

FIELD: pharmacology, in particular pharmaceutical composition for obesity prophylaxis and treatment.

SUBSTANCE: invention relates to claimed composition containing crystalline sibutramine methanesulfonate hemihydrate, as well as methods for production and uses of crystalline sibutramine methanesulfonate hemihydrate.

EFFECT: product with improved solubility.

12 cl, 5 dwg, 5 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel analogs of fatty acids of the general formula (I): R1-[Xi-CH2]n-COOR2 wherein R1 represents (C6-C24)-alkene with one or more double bond, and/or (C6-C24)-alkyne; R2 represents hydrogen atom or (C1-C4)-alkyl; n represents a whole number from 1 to 12; I represents an uneven number and shows position relatively to COOR2; Xi is chosen independently of one another from the group comprising oxygen (O), sulfur (S) and selenium (se) atom and -CH2 under condition that at least one among Xi is not -CH2 and under condition that if R1 represents alkyne then a carbon-carbon triple bond is located between (ω-1)-carbon atom and (ω-2)-carbon atom, or between (ω-2)-carbon atom and (ω-3)-carbon atom, or between (ω-3)-carbon atom and (ω-4)-carbon atom, and to their salts and complexes. The claimed compounds can be used in treatment and/or prophylaxis of X syndrome, obesity, hypertension, hepatic fatty dystrophy, diabetes mellitus, hyperglycemia, hyperinsulinemia and stenosis. Also, invention relates to methods for preparing novel analogs of fatty acids. Also, invention relates to a nutrient composition comprising indicated analogs of fatty acids and to a method for reducing the total body mass or amount of lipid tissue in humans or animals. Invention provides the development of novel fatty acid analogs-base compositions or methods for suppression of stenosis, restenosis or associated disorders as result of proliferation and mobilization of vessel smooth muscle cells after, for example, traumatic damages of vessels during surgery operation in vessels.

EFFECT: improved preparing method, valuable medicinal properties of analogs.

12 cl, 2 dwg, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel condensed cyclopropylpyrrolidines of the formula: wherein x means 0 or 1 and y means 0 or 1 under condition that x means 1 when y means 0, and x means 0 when y means 1; and wherein n means 0 or 1; X means hydrogen atom (H) of group -CN; R1, R2, R3 and R4 are similar or different and chosen independently from H, (C1-C10)-alkyl, (C2-C12)-alkenyl, saturated (C3-C10)-cycloalkyl, saturated (C3-C10)-cycloalkyl-(C1-C10)-alkyl, saturated (C3-C10)-bicycloalkyl, saturated (C3-C10)-tricycloalkyl, hydroxyl-(C1-C10)-alkyl-saturated (C3-C10)-cycloalkyl, (C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkylthio-(C1-C10)-alkyl, (C6-C10)-aryl-(C1-C10)-alkyl, 5- or 6-membered heteroaryl comprising one nitrogen atom (N) or one oxygen atom (O), 5- or 6-membered heteroaryl comprising one atom N condensed with (C6-C10)-aryl ring, 5- or 6-membered heteroaryl comprising one atom N or one atom O, (C1-C10)-alkyl, cycloheteroalkyl that represents (C5-C8)-saturated ring comprising one heteroatom, such as N or O; if necessary, all compounds comprise 1, 2, 3, 4 or 5 groups of substitutes at corresponding carbon atom chosen from halogen atom, (C1-C10)-alkyl, (C2-C12)-alkenyl, hydroxy-group, hydroxy-(C1-C10)-alkyl or cyano-group; R1 and R4 can form in common, if necessary, the group -(CR5R6)m- wherein m means 2-6, and R5 and R6 are similar or different and chosen independently from hydroxy-group, H or (C1-C10)-alkyl including all their stereoisomers; and their pharmaceutically acceptable salt, or prodrug esters and all their stereoisomers. These compound inhibit activity of dipeptidyl peptidase IV that allows their using in pharmaceutical compositions used in treatment of diabetes mellitus of type-2.

EFFECT: valuable medicinal properties of compounds.

20 cl, 6 tbl, 113 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with treating obesity of different genesis. One should regulate patient's appetite and body weight, and, also, lipid exchange with the help of chromium ions. For this purpose one should apply chromium oxide (VI) at the dosage of 0.35 mg/kg/d in drops in the form of solution. The suggested dosage corresponds to maximal curative action of this microelement. The innovation in question enables to adequately control chromium entrance into the body depending upon body weight, patient's sensitivity to therapy due to dosing by drops and has no side effects and contraindications.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: invention relates to method for decreasing of nutrient availability, method for appetite suppression or reducing of food consumption. Claimed method includes application of PYY substance (YY peptide) or PYY agonist in peripheral administration. Method provides decreasing of nutrient availability in mouse females hungered for one night, reducing stomach ejection, inhibition of acid secretion in stomach, preventing cholecyst ejection, and inhibition of amylase secretion in pancreas.

EFFECT: preparation for decreasing of nutrient availability of improved effect.

35 cl, 10 ex, 8 dwg, 1 tbl

FIELD: medicine, in particular compounds with de novo lipogenesis inhibitor activity useful in treatment and/or prophylaxis of obesity.

SUBSTANCE: claimed method includes methods (variants) for screening of compounds which are capable of inhibit at least one carbonic anhydrase activity in mammalian organism and having no anticonvulsant activity. Also is disclosed production of pharmaceuticals for treatment and/or prophylaxis of obesity containing said compounds.

EFFECT: new method for screening pharmaceuticals for treatment and/or prophylaxis of obesity on the base of their carbonic anhydrase inhibitor activity.

17 cl

FIELD: food additives.

SUBSTANCE: it has been developed both the dietetic composition and method in which one should apply the foundation as food for mammalians and an active component being an estrogen, androgen or their mixture at the quantity to be sufficient for preventing body weight gain usually happened in mammalians after delayed maturation of reproductive organs, castration, ovariectomy or hysterectomy, or during post-climacteric period. Preferably, active component is being a phytoestrogen, phytoandrogen or their mixture, at the quantity 0.001-10 weight% against the weight of composition. Application of compositions efficiently prevents body weight gain in mammalians.

EFFECT: higher efficiency.

4 ex, 3 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

Healthy toothpaste // 2297212

FIELD: stomatology, in particular agents for oral cavity care.

SUBSTANCE: claimed paste contains glycerol, sorbitol, abrasive and thickening silica, sodium lauryl sulfate table salt, xanthan gum, non-encapsulated and encapsulated flavoring, alkylamidobetaine, carboxyvinyl polymer, triclosan, sodium methylparaben, sodium propylparaben, sodium saccharine, food-grade colorant, sodium hydroxide, and water in specific component ratio.

EFFECT: toothpaste of improved quality due to combination of anti-caries component, anti-bacterial system, flavorings and mineral complex.

2 ex, 1 tbl

FIELD: food-processing, biotechnological and medical industry.

SUBSTANCE: yeast-based biologically active substance is produced as chelate complex based on yeast fermentalisate containing at least 60 wt% of peptide fraction with molecular weight exceeding 2.5 kda, at least 14 wt% of free amino acids, at least 8 wt% of amino nitrogen, about 20 wt% of carbohydrates, at least 14 wt% of dry substance. Fermentalisate is produced by fermentative autolysis of Saccaromyces cerevisiae at temperature of 45-60 C and pH of 3-5, cooling to 30-40 C, accompanied by processing with enzyme preparation of lactocanicin. Resultant yeast fermentalisate is cleaned from residual cellular enclosure structures, desalinated and exposed to chelation carried out by preparing 10%-solution of cleaned yeast fermentalisate, followed by microfiltering of solution and obtaining clarified fraction. The latter is treated with 50%-solution of chloride of metals selected from the group consisting of Zn++, Cu++, Mn++, Cr+++, Fe++, with the ratio of yeast fermentalisate solution to aqueous solution of metal salt of (0.5-3):(0.001-2). Acidity of solution is brought to 6.5-7.9 and the latter is held during 0.5-1.5 hours at 15-35 C while being mixed. Resultant solution is subjected to microfiltering for producing of clarified fraction, wherein phosphate buffer of alkaline metal is added and mixed, and mixture is held during 15-50 min at temperature of 15-35 C, followed by microfiltering, obtaining of clarified fraction and drying it so that free metal is present in ready product in an amount not in the excess of 2% by weight of ready product. Biologically active food additive contains said biologically active substance and component selected from the group consisting of hydrocarbons, lipids, vitamins, vitamin-like substances, mineral components, alkaloids, homeopathic means, glycosides, immunoglobulin preparations, phenol compounds, organic acids, enzymes, terpenoids, hormones and hormone-like substances, cytokine, plant products, microbic products, apiculture products, animal products, mineral-containing natural substances, detoxicants, process additives, or mixtures thereof with the following component ratio, wt%: biologically active food additive 10-95; component or mixture of components the balance.

EFFECT: enhanced biological effect, convenient usage, and non-toxicity owing to reduced residue of free metal in product.

5 cl, 4 ex

FIELD: food processing industry, biotechnology, medicine industry, in particular production of bioactive substances.

SUBSTANCE: yeast-based bioactive substance (BAS) represents fermentolysate obtained by autolysis of optionally selenium-containing Saccaromyces cerevisiae at 45-60°C and pH 3-5, cooling to 30-40 °C followed by treatment with enzyme preparation lactocanicine. Said fermentolysate contains at least 60 % of peptide fraction with molecular weight more than 2.5 kDa; free amino acids at least 14 %; amine nitrogen at least 8 %; carbohydrates at most 20 %; dry matter at least 14 %. Bioactive food supplement contains bioactive substance and component selected from carbohydrates, lipids, vitamins, vitamin-like substances, alkaloids, mineral components, homeopathic agents, glycosides, immunoglobuline preparations, phenol compounds, organic acids, enzymes, terpenoids, hormones and hormone-like substances, etc., in mass ratio: BAS 10-95 % and balance: component mixture.

EFFECT: non-toxic BAS having high biological activity, hypoallergic properties, useful in prophylaxis and treatment of various diseases.

7 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

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